Ebony Liu1, Georgia Kaidonis1, Bennet J McComish2, Mark C Gillies3, Sotoodeh Abhary1, Rohan W Essex4, John H Chang5,6, Bishwanath Pal6, Mark Daniell7, Stewart Lake1, Nikolai Petrovsky8, Alex W Hewitt9, Alicia Jenkins10,11, Ecosse L Lamoureux9,12,13, Jonathan M Gleadle14, Jamie E Craig1, Kathryn P Burdon1,2. 1. Department of Ophthalmology, Flinders University, College of Medicine and Public Health, Flinders Medical Centre, Adelaide, South Australia, Australia. 2. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. 3. Save Sight Institute, Clinical Ophthalmology and Eye Health, the University of Sydney, Sydney, New South Wales, Australia. 4. Academic Unit of Ophthalmology, Australian National University, Canberra, Australia. 5. School of Medical Sciences, University of NSW, Sydney, New South Wales, Australia. 6. Medical Retina Service, Moorfields Eye Hospital, London, United Kingdom. 7. Department of Ophthalmology, Royal Melbourne Hospital, Melbourne, Victoria, Australia. 8. Department of Endocrinology, Flinders University, Flinders Medical Centre, Adelaide, South Australia, Australia. 9. Centre for Eye Research Australia, University of Melbourne, Melbourne, Victoria, Australia. 10. NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. 11. St. Vincent's Hospital, Fitzroy, Victoria, Australia. 12. Singapore Eye Research Institute, Singapore. 13. Duke-NUS Medical School, Singapore. 14. Renal Medicine, College of Medicine and Public Health, Flinders University, Flinders Medical Centre, Adelaide, South Australia.
Abstract
Purpose: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). Methods: All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Results: Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Conclusions: Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.
Purpose: Few studies have explored the association of genetic variants in microRNA genes and binding sites with diabetic retinopathy (DR) in type 1 diabetes. We conducted a genome-wide scan for single nucleotide polymorphisms (SNPs) in these genes by using data from a genome-wide association study (GWAS). Methods: All known SNPs were imputed from our GWAS data (n = 325) of DR cases and diabetic controls (no DR). Relevant SNPS were extracted using miRNASNP and PolymiRTS (version 2) databases. χ2 tests and logistic regression (adjusting for age, sex, duration of diabetes, HbA1c, and hypertension) were used to test the association between the imputed SNPs and DR phenotypes (any DR, nonproliferative DR [NPDR], proliferative DR [PDR], diabetic macular edema [DME], and sight-threatening DR defined as PDR, severe NPDR, or clinically significant macula edema [CSME]) compared with diabetic controls. Top-ranking SNPs were genotyped in a larger cohort (N = 560) to confirm their association with DR. Results: Three SNPs (rs10061133, rs1049835, rs9501255) were selected and genotyped in the final cohort. Rs10061133 in MIR449b was protective of sight-threatening DR (odds ratio [OR] = 0.32, P = 3.68 × 10-4) and PDR (OR = 0.30, P = 8.12 × 10-4), and the associations became more significant as the cohort increased in size. Conclusions: Rs10061133 in MIR449b is significantly associated with a decreased risk of PDR and sight-threatening DR in Caucasian patients with type 1 diabetes. This can guide future studies on genetic risk profiling and on developing microRNA-related therapies for sight-threatening DR.